Stabilization of ATF4 protein is required for the regulation of epithelial-mesenchymal transition of the avian neural crest.

Epithelial-mesenchymal transition (EMT) permits neural crest cells to delaminate from the epithelial ectoderm and to migrate extensively in the embryonic environment. In this study, we have identified ATF4, a basic-leucine-zipper transcription factor, as one of the neural crest EMT regulators. Although ATF4 alone was not sufficient to drive the formation of migratory neural crest cells, ATF4 cooperated with Sox9 to induce neural crest EMT by controlling the expression of cell-cell and cell-extracellular matrix adhesion molecules. This was likely, at least in part, by inducing the expression of Foxd3, which encodes another neural crest transcription factor. We also found that the ATF4 protein level was strictly regulated by proteasomal degradation and p300-mediated stabilization, allowing ATF4 protein to accumulate in the nuclei of neural crest cells undergoing EMT. Thus, our results emphasize the importance of the regulation of protein stability in the neural crest EMT.